Recommends

Comments

This paper supports our recently described studies on Aβ-binding alcohol dehydrogenase (ABAD), Aβ, and mitochondrial toxicity (see Lustbader et al., 2004; Caspersen et al., 2005; and Takuma et al., 2005). In our Science paper (see Lustbader et al., 2004), we first described that Aβ is present in mitochondria and forms a complex with ABAD. We have extended these studies and analyzed Aβ-mediated mitochondrial dysfunction in the brains from patients with Alzheimer disease (AD) and AD-type mouse models. The studies (see Caspersen et al., 2005) showed how Aβ progressively accumulates in the mitochondria in brains of AD patients and also in transgenic mice overexpressing mutant APP. The accumulation of Aβ occurred as early as 4 months before plaque formation. Most importantly, we found that the major species of Aβ in the organelles was Aβ1-42. We reported that the levels of mitochondrial Aβ42 were five- to sixfold higher than Aβ40. We also found that oligomeric Aβ (more toxic form) was present in mitochondria, and that the presence of Aβ was associated with dysfunction of the organelles.

In using a different mouse model (Tg2576 mice generated by Karen Ashe versus the J-20 line developed by Lennart Mucke that we used), Manczak et al. offer further substantial support for our hypothesis that mitochondria serve as a direct target for amyloid-mediated cellular perturbation.

Taken together, increased evidence supports that mitochondria are central players for Aβ-induced cellular perturbation relevant to Alzheimer disease. Mitochondria provide a site for accumulation of intraneuronal Aβ, which interferes with mitochondrial function leading to neuronal perturbation. Blockade of accumulation of Aβ in mitochondria or interception of its interaction with mitochondrial targets such as ABAD might be a therapeutic approach for treatment of AD.